An overactive bladder refers to a disease with symptoms of urinary frequency, urinary urgency or urgent urinary incontinence. Urinary frequency is a need to urinate more than usual, mostly more than eight times a day, and still having the desire to urinate even when the bladder is not full. Urinary urgency is a sudden strong uncontrollable urge to urinate. Urgent urinary incontinence is a condition of involuntary leakage of urine. Excessively frequent contraction of the smooth muscle of the bladder (detrusor muscle) is presumed to be a cause of overactive bladder. That is, the bladder muscle contracts more frequently than normal or when unnecessary, causing a sudden uncontrollable urge to urinate before the bladder is full. Most causes of such bladder muscle contraction remain unknown. In some cases, symptoms of an overactive bladder develop due to problems in neurotransmission from the brain to the bladder or neuronal damage arising from surgery or parturition. For males, overactive bladder diseases may be accompanied by prostatic hyperplasia.
Overactive bladder can lead to lack of sleep, reduced work efficiency, avoidance of sexual life, and depression. Overactive bladder can eventually lead to a poor quality of life due to lack of information concerning overactive bladder and feelings of shame.
U.S. Pat. No. 5,382,600 discloses (substituted) 3,3-diphenylpropylamines useful for the treatment of urinary incontinence. Particularly, this patent describes that 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol, which has a general name of tolterodine and is known as N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine, is useful for the treatment of urinary incontinence. Tolterodine is currently used in the form of an acid addition salt with a pharmaceutically acceptable acid. A tolterodine acid addition salt commercially available for the treatment of overactive bladder is tolterodine tartrate.
Presently, anticholinergic drugs account for most therapeutic drugs for overactive bladder. However, anticholinergic drugs have side effects, such as dry mouth, constipation and disturbance of consciousness, which serve as great barriers to patients with overactive bladder in need of long-term administration. Particularly, the administration of anticholinergic drugs increases the risk of urinary obstruction in patients with prostatic hyperplasia and is prohibited in patients with dementia and patients with glaucoma. Under these circumstances, there is a need to develop a novel therapeutic drug or a pharmaceutical drug delivery system that can improve the quality of life. One approach to reduce the side effects of a therapeutic drug for overactive bladder is to biopharmaceutically control the blood level of the drug above a minimum effective concentration and below a concentration at which the side effects occur. For this approach, studies on sustained-release pharmaceutical drug delivery systems are much underway. Currently commercially available dosage forms of tolterodine are film-coated tablets containing 1 mg, 2 mg or 4 mg of tolterodine L-tartrate that is released in the gastrointestinal tract upon administration.
Transdermal drug delivery systems are technologies by which drugs are absorbed through the skin. Transdermal drug delivery systems have particular advantages of reduced side effects, particularly, in the gastrointestinal tract, bypass of hepatic first pass and enhanced convenience of administration to patients due to their ability to maintain the concentration of drugs at a constant level compared to other drug delivery systems. Therefore, transdermal drug delivery systems can be considered an optimal system to reduce the side effects of therapeutic drugs for overactive bladder and enhance the convenience of administration to patients.
U.S. Pat. No. 6,517,864 discloses that transdermal administration of tolterodine is useful for the treatment of overactive bladder. Particularly, this patent discloses that small doses and short half-life make tolterodine favorable as a drug for transdermal administration and tolterodine in the form of free base is more effective in skin penetration than tolterodine in the form of an acid addition salt with a pharmaceutically acceptable acid. However, the skin absorption rate (permeability) of tolterodine is very low, which needs to be increased.